Recent studies have provided compelling evidence that loss-of-function mutations in the CHD8 gene, which encodes an ATP-dependent chromatin-remodeling factor, are associated with an autism subtype characterized by macrocephaly, specific craniofacial features and gut immobility. The CHD8 protein modifies the structure of chromatin in the cell nucleus, and in vitro studies have suggested that CHD8 might function as a regulator of the developmentally important Wnt and PTEN signaling pathways. Tight control of both of these pathways is critical for normal brain development, and mutations that affect their activity have been strongly associated with autism and brain size. It is therefore important to test whether CHD8 functions as a regulator of these pathways during brain development.

Albert Basson and his colleagues at King’s College London have produced new mouse lines with reduced CHD8 function throughout the whole developing embryo to model the human loss-of-function condition. The researchers have also generated mice with CHD8 deleted specifically from the developing brain to determine the functions of CHD8 during development. As individuals with CHD8 mutations have larger heads, suggestive of brain overgrowth, Basson and his team will test whether CHD8 controls the growth of the brain and assess the mechanisms by which CHD8 controls brain development. Initial experiments will examine the effect of reductions in, or loss of, CHD8 function on Wnt and PTEN pathways at critical stages of brain growth and development. The team will then employ genetic experiments to determine whether Wnt or PTEN pathway deregulation is responsible for disrupted brain development and abnormal social behaviors in CHD8 mutant mice.

The availability of these new mouse models will allow researchers to identify new phenotypes and mechanisms that underlie developmental anomalies associated with CHD8 dysfunction. Furthermore, these models may also prove valuable in the evaluation of potential therapies to ameliorate neurodevelopmental abnormalities and restore social difficulties associated with autism.